Study mimicked typical antibiotic course in childhood

Action Points

Early-in-life antibiotics, based on doses and pharmacokinetics used in young children, can increase autoimmune diabetes development in non-obese diabetic (NOD) mice that spontaneously develop autoimmune (T1D-like) diabetes.

Note that in other studies, antibiotics were found to have the opposite effects; thus, antibiotic type, dose, and timing are all relevant variables that might influence effects.

Results of a study in mice suggest that antibiotic therapy early in life alters gut microbiota, T-cell populations, and gene expression in a way that leads to type 1 diabetes.

In experiments with male non-obese diabetic (NOD) mice, which are genetically predisposed to a condition closely resembling type 1 diabetes, those that received pulsed antibiotic therapy during the first 6 weeks of life developed the condition at twice the rate seen in control mice (53% versus 26%; P<0.05), reported Martin Blaser, MD, of the New York University School of Medicine, and colleagues.

The composition of gut microbes in the antibiotic-treated mice of both sexes differed significantly from controls. Especially notable was the absence of Bifidobacterium, Blaser and colleagues reported in Nature Microbiology.

In the male antibiotic-treated mice, the proportions of regulatory T cells and Th17 cells in the gut were significantly lower than controls, the investigators said.

"Our study begins to clarify the mechanisms by which antibiotic-driven changes in gut microbiomes may increase risk for type 1 diabetes," Blaser said in a statement. "This work uses NOD mice, the best model of type 1 diabetes to date, and doses of antibiotics like those received by most children to treat common infections."

"This work shows that early-in-life antibiotic exposure in NOD mice can accelerate T1D development, modifying the disease," the investigators said. "This study, along with other recent investigations, raises questions regarding widespread antibiotic use in early childhood."

"However," they added, "in other studies, antibiotics were found to have the opposite effects; thus, antibiotic type, dose, and timing are all relevant variables that might influence effects."

The investigators randomized the mice to a control group, a group that received continuous low-dose antibiotics, and a group that received pulsed antibiotic therapy designed to mimic the antibiotic therapy a human might receive in childhood. This therapy consisted of a 50 mg/kg daily dose of macrolide tylosin tartrate delivered in drinking water at days 10-15, 28-31, and 37-40 of the mice's lives.

"The pulsed antibiotic therapy model is clinically relevant, because U.S. children receive approximately one antibiotic course annually, frequently macrolides," Blaser and colleagues said.

A subset of mice were killed at 6 weeks of age and analyzed for microbiota composition, T cells, and gene expression in the gut. Other mice were tested weekly for diabetes via blood glucose measurements from 10 to 31 weeks of age.

Gut microbe composition was significantly altered in treated mice of both sexes, but higher type 1 diabetes prevalence, altered T cell proportions, and altered gene expression occurred only in the male mice, likely reflecting a gender difference in the progression of the disease, Blaser and colleagues said.

The most dramatic differences were found between the control mice and the mice treated with pulsed antibiotic therapy, the investigators noted. Differences in the low-dose antibiotic group were more modest. For example, there was no significant difference in type 1 diabetes prevalence in the low-dose antibiotic group compared with controls, they said.

Gut microbe biodiversity in pulse antibiotic-treated mice was approximately one-third that of control mice at week 3 (P<0.01). However, after antibiotic treatment stopped at week 6, the biodiversity increased to approximately two-thirds that of the control mice by week 13.

Regarding the absence of Bifidobacterium in the treated mice, the investigators said, "In humans and other mammals, more than 30 Bifidobacterium species have been identified, and broad conservation suggests functional importance. Bifidobacterium species dominate the gut microbiota of healthy infants, especially when breast-fed, consistent with Bifidobacterium digesting breast milk oligosaccharides."

The proportion of CD4+ FOXP3+ T-regulatory cells in the small intestinal lamina propria of treated male mice was less than 10%, compared with more than 15% in the control group (P<0.01), Blaser and colleagues reported. The proportion in the low-dose continuous antibiotic group was about 10%. The study found a similar pattern for Th17 cells.

The investigators also noted altered ileal gene expression in the pulse antibiotic-treated male mice compared with controls. Most notable was the downregulation of the serum amyloid A genes, thought to play a role in immune system function.

"Further studies will help understand generalizability, pathway independence or synergy, and whether such pathways can be modified to prevent or delay T1D development," they added.

The study was funded by the Juvenile Diabetes Research Foundation, the Diane Belfer Program for Human Microbial Ecology, the Howard Hughes Medical Institute, the Defendi Fellowship, the Knapp Family, the Ziff Family, and C&D Funds.

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